Research proposals developed in this Program Prqject will characterize the mechanisms responsible for the cardioprotective effects of volatile anesthetics against ischemia and reperfusion iniury in vivo, and will directly elucidate mechanisms regarding the specific signal transduction pathways modulated in vitro. It is our belief that the most effective approach to the complex and clinically relevant issue of myocardial ischemia and its response to anesthetics is to integrate our studies at multiple levels. We propose a Program Project consisting of three interrelated research projects supported by a Core facility focused on fundamental mechanisms responsible for the cardioprotective effects of volatile anesthetic-induced preconditioning (APC). This integrative approach will not only bring together a multi-talented group of investigators including cardiac electrophysiologists and molecular biologists, but also will capitalize on the unique advantage of interactions amongst the Cardiovascular Research Center, Biophysics Research Institute and the Departments of Pharmacology, Physiology, Biochemistry and Anesthesiology at the Medical College of Wisconsin. Project I. ANESTHETIC-INDUCED PRECONDITIONING IN VIVO. This project will delineate mechanisms responsible for the novel cardioprotective effects of volatile anesthetics against ischemia and reperfusion injury in vivo and will provide initial evidence for the involvement of specific signal transduction pathways modulating APC. Project Director: David C. Warltier, M.D., Ph.D. Project II. CARDIAC K,T, CHANNELS IN ANESTHETIC-INDUCED PRECONDITIONING. This prqject will investigate the effects of APC on the response of native sarcolemmal and mitochondfial KATp channels in cardiac ventricular myocytes, expressed recombinant KATp channels and channels in a lipid bilayer to nucleotides and potassium channel openers and blockers. Project Director: Zeljko J. Bosnjak, Ph.D. Project III. CARDIAC ELECTROPHYSIOLOGY IN ANESTHETIC-INDUCED PRECONDITIONING. This project will characterize arrhythmias and the ionic mechanisms underlying volatile anesthetic action on cardiac electrophysiology including major voltage-gated ion channel types (fast Na channel, L-type Ca channel, and transient outward K channel) that may ultimately be directly or indirectly involved in APC. Project Director: Wai-Meng Kwok, Ph.D. BIOCHEMICAL AND MOLECULAR BIOLOGY CORE. The Biochemical and Molecular Biology Core of this Program Prqiect will provide a highly specialized team of professional staff, capable of organizing a variety of assays in a well equipped facility to support investigation of hypotheses developed in Projects I, II and III. Core Directors: Meetha Medhora. Ph.D. and David Harder. Ph.D.